Infections and/or inflammations of the gut are very common, especially in infants and young children because of their weak conditions, a relatively poor hygiene and their immature immune defences. Defense mechanisms involve the establishing of a commensal microbiota and of an innate and adaptive immune system. In the first 2 to 3 years of life of an individual, these defense systems are not fully established, making infants more vulnerable to infections. Pathogens may therefore able to overcome the defense mechanisms of the infants and young children. For example, in the first year of life, an infant will often experience from one to four gastrointestinal infections/inflammations.
There can be infections of the upper gastrointestinal tract, e.g. infections of the oesophagus and/or stomach. The infections may also be located in the lower gastrointestinal tract, e.g. infections of the small intestine and all of the large intestine (colon). Examples of gastrointestinal infections are enteritis, gastroenteritis, infectious diarrhea. The gut infections may also be associated with gut inflammation. This is especially the case for enteritis, gastroenteritis, infectious diarrhea.
Enteritis refers to an infection of the small intestine. It is often associated with an inflammation of the small intestine. Gastroenteritis or infectious diarrhea is a medical condition of the gastrointestinal tract that involves both the stomach and the intestine. It is also generally associated with an inflammation of these organs.
The main symptoms of the gastrointestinal infections are diarrhea, vomiting, abdominal pain and cramping. There may also be feeding difficulties, irritability, poor sleep, tiredness, but also headache and fever especially if it has a viral origin. Dehydration may occur as a result.
The gastrointestinal inflammations relate to inflammations involving the gastrointestinal tract. Similarly, there can be inflammations of the upper gastrointestinal tract or of the lower gastrointestinal tract. Examples of gastrointestinal inflammations are enterocolitis, NEC (necrotizing enterocolitis) and oesophagitis. As indicated in the previous paragraph, the gastrointestinal infections may also be associated with a gastrointestinal inflammation.
Enterocolitis is an inflammation of the digestive tract, involving the small intestine and the colon. Common clinical manifestations of enterocolitis are frequent diarrheal defecations, with or without nausea, vomiting, abdominal pain, fever, chills, alteration of general condition. General manifestations are given by the dissemination of the infectious agent or its toxins throughout the body, or most frequently by significant losses of water and minerals, the consequence of diarrhea and vomiting.
Necrotizing enterocolitis (NEC) is a medical condition primarily seen in premature infants, where portions of the bowel undergo necrosis (tissue death). It occurs postnatally and it is the second most common cause of mortality in premature infants. Initial symptoms include feeding intolerance, increased gastric residuals, abdominal distension and bloody stools. The symptoms may progress rapidly to abdominal discoloration with important gut necrosis, intestinal perforation, peritonitis, systemic hypotension requiring intensive medical support, need of a surgical intervention, and sometimes death.
Oesophagitis is an inflammation of oesophagus. Clinical manifestations are pain, sialorrhea, odynophagia and/or dysphagia. The complications could be bleeding, iron deficiency and/or stenosis.
The gastrointestinal infections/inflammations may have a bacterial origin, a viral origin, a fungal origin, a parasitical origin or any other origins such as an environmental origin. Viruses (particularly rotavirus) and the bacteria Escherichia coli and Campylobacter species are the primary causes of gastroenteritis. There are, however, many other infectious agents that can cause this syndrome, but non-infectious causes (e.g. environmental causes) may also be seen on occasion.
Rotavirus, norovirus, adenovirus, and astrovirus are known to cause viral gastroenteritis.
In the developed world Campylobacter jejuni is the primary cause of bacterial gastroenteritis, with half of these cases associated with exposure to poultry. In children, bacteria are the cause in about 15% of cases, with the most common types being Escherichia coli, Salmonella, Shigella, and Campylobacter species.
A number of protozoans (parasites) can cause gastroenteritis, most commonly Giardia lamblia, but also Entamoeba histolytica and Cryptosporidium species. As a group, these agents comprise about 10% of cases in children.
Enterocolitis may similarly be caused by various infections, with bacteria, viruses, fungi, parasites, or other causes.
There may also be gut infections/inflammations due to toxins (e.g. from clostridium difficile).
There may also be infections/inflammations due to opportunistic pathogens for example in situations of dysbiosis e.g. following an antibiotic treatment.
There are also a number of non-infectious (e.g. environmental) causes of inflammation of the gastrointestinal tract. Some of the more common include medications (like NSAIDs), certain foods such as lactose (in those who are intolerant), and gluten (in those with celiac disease). Disease secondary to pollution or to Crohn's disease may also occur. Some foods commonly associated with illness include raw or undercooked meat, poultry, seafood, eggs, raw sprouts, unpasteurized milk and soft cheeses, fruit and vegetable juices, but also ciguatera poisoning due to consumption of contaminated predatory fish, scombroid associated with the consumption of certain types of spoiled fish, tetrodotoxin poisoning from the consumption of puffer fish among others, and botulism typically due to improperly preserved food.
In infants and young children, the origin of oesophagitis may be peptic (caused by the reflux of acid) but other origins have been described such as caustic, radiation induced, following an infection, drug induced (antibiotic, NSAID . . . ) or inflammatory (e.g. Crohn's disease).
Mother's milk is recommended for all infants. However, in some cases breast feeding is inadequate or unsuccessful for medical reasons or the mother chooses not to breast feed. Infant formulae have been developed for these situations. Fortifiers have also been developed to enrich mother's milk or infant formula with specific ingredients.
Hence, there is a need to establish nutritional solutions especially for infants and young children who cannot always be breastfed that will help to protect them from the gut inflammations/infections, especially those triggered by bona fide and opportunistic pathogens.
Acting directly onto the pathogens, for example via antibiotics, might be one solution of choice in specific cases. However, in most cases of gastrointestinal infection/inflammation, this could have a negative effect as also commensal microbiota are affected by the treatment and those commensals are an important contributor to defense via a mechanism dubbed colonization resistance. This antibiotics treatment will also not be efficient on viral infections. There are also important issues regarding the emerging resistance of bacteria to the antibiotics treatments.
There is thus clearly a need for alternative methods to decrease the incidence of these painful and potentially serious health conditions in infants and young children.
Many attempts have been made to develop alternative pathways to prevent/treat infections and/or inflammations of the gut. The use of probiotics has especially been investigated. Probiotics are considered to be viable microbial preparations which promote the individual's health by preserving the natural microflora in the intestine. Probiotics are deemed to attach to the intestine's mucosa, colonize the intestinal tract and likewise prevent attachment of harmful microorganisms thereon. A crucial prerequisite for their action resides in that they have to reach the gut's mucosa in a proper and viable form and do not get destroyed in the upper part of the gastrointestinal tract, especially by the influence of the low pH prevailing in the stomach.
For example WO2004001022 from the University of Newcastle Research provides methods for treating health conditions such as gastrointestinal diseases using the strain Propionibacterium jensenii 702.
Other routes than probiotics have been explored such as the use of prebiotics, and especially human milk oligosaccharides. Human milk oligosaccharides (HMOs) are, collectively, the third largest solid constituents in human milk, after lactose and fat. HMOs usually consist of lactose at the reducing end with a carbohydrate core that often contains a fucose or a sialic acid at the non-reducing end. There are over one hundred milk oligosaccharides that have been isolated and characterized in human milk.
Several compositions have therefore been developed using HMO ingredients, such as fucosylated oligosaccharides, lacto-N-tetraose, lacto-N-neotetraose, and for different purposes.
For example WO2005055944 from Children's hospital medical center describes a pharmaceutical composition comprising a molecule comprising a fucose group in an alpha-2 linkage, an alpha-3 linkage or an alpha-4 linkage to a galactose group and a pharmaceutically acceptable carrier. Various molecules are described such as 2′-fucosyllactose. This application is quite general since several infections can be prevented or treated, including enteric infections, and there is a large target of patients (infants, children or adults).
WO2004002495 describes an oligosaccharide-containing substance or receptor binding to diarrheagenic Escherichia coli and/or zoonotic Helicobacter species, and use thereof in, e.g., pharmaceutical, nutritional and other compositions for prophylaxis and treatment of diarrhea, hemorrhagic colitis or haemolytic uremic syndrome.
WO9956754 from Abbott relates to compositions containing at least one fucose residue in an alpha 1-2 linkage such as 2FL and uses thereof. In particular, such compositions can be used in the treatment and prevention of gastrointestinal infections like diarrhoea and enterocolitis.
US2014248415 describes several examples of HMOs mixtures, some including both 2FL and LNnT in various ratios. They may be used for various health benefits such as immune system maturation, allergy, influenza, diarrhea.
As disclosed in WO9843494 from Abbott, oligosaccharides in general are known to have effects against infections from the respiratory, gastrointestinal urogenitial tracts. It gives several examples of HMOs alone or in combination without associating a particular type of oligosaccharides or synergic associations thereof to a particular benefit.
Most of the prior art documents however indicate compositions with different types of HMOs in various concentrations that may not be specifically adapted to the infant needs (e.g. in concentrations that are very different to the ones found in breast milk for example).
WO9843495 from Abbott relates to a process for inhibiting Bacteroides, Clostridium and E. coli infection in a subject comprising feeding the subject a synthetic nutritional formulation that contains an effective anti-bacterial amount of Lacto-N-neoTetraose. By inhibiting the growth of these bacteria, infants are provided with resistance against gastroenteritis.
Further studies were specifically focused on various associations of HMOs with a probiotic strain.
For example WO2009077352 from Nestec SA relates to compositions comprising Bifidobacterium with fucosylated oligosaccharides for the prevention of opportunistic infections in immune-compromised individuals. The opportunistic infection may be an infection of the respiratory, urinary or gastrointestinal tract.
WO2009112361 from Nestec SA discloses preparation comprising N-acetyl-lactosamine and/or an oligosaccharide containing N-acetyl-lactosamine and a probiotic Lactobacillus sp for the use of the preparation in the prevention and treatment of pathogenic infections of the gastro-intestinal and upper respiratory tracts.
So most of the prior art documents refer to compositions that can be used for health conditions located at various body parts (respiratory, urinary, gut tract . . . ) so they are not necessarily focused on or specifically adapted to gastrointestinal infections/inflammations. Some others only refer to infections of bacterial origin and it can be expected that the proposed nutritional solutions would not be efficient on other types of infections due to a targeted action directly against the responsible bacteria.
There is therefore a need to develop nutritional compositions that will be particularly efficient and adapted to prevent or treat gastrointestinal infections/inflammations, whatever their origin (bacterial, viral, fungal, parasitic, environmental or any other origins) and in the same time efficient on a wide array of gut conditions (enteritis, gastroenteritis, infectious diarrhea, enterocolitis, NEC, oesophagitis).
There is clearly a need for developing suitable methods to decrease the incidence of these health conditions in infants and young children.
There is also a need to deliver such health benefits in a manner that is particularly suitable for the young subjects (infants and young children), in a manner that does not involve a classical pharmaceutical intervention as these infants or young children are particularly fragile.
There is a need to deliver such health benefits in these infants or young children in a manner that does not induce side effects and/or in a manner that is easy to deliver, and well accepted by the parents or health care practitioners.
There is also a need to deliver such benefits in a manner that does keep the cost of such delivery reasonable and affordable by most.
There is thus clearly a need to develop alternative methods than the classical pharmaceutical intervention such as the use of antibiotics, at least because of the previously mentioned issues of resistance development.
There is also a need to develop an alternative treatment pathway that may be efficient for a broad range of origins, i.e. independently of the causes of the infections and/or inflammations (e.g. bacterial, viral, fungal, parasitical, environmental or any other origins).